Abstract Breast cancer is the most frequently diagnosed cancer among women, and the second leading cause of cancer death among women. The 5-year survival rate for breast cancer patients with localized disease is 98.7%, however with metastatic spread survival decreases to 27%. This difference in survival highlights a vital need for development of therapies targeting metastatic disease in order to improve outcomes in breast cancer patients. The Th2 cytokine interleukin-4 (IL4) has a number of established roles in immune cells. These effects include increasing glucose metabolism in B-lymphocytes, inducing fatty acid oxidation in macrophages, and regulation of epigenetic alterations that impact polarization of macrophages. The role of IL4 in cancer has largely been studied from the perspective of its effects on immune cells in the tumor microenvironment. A number of epithelial cancers, including breast cancer, express interleukin-4 receptor (IL4R). However, the effects of IL4 on IL4R expressing cancers are not as well understood as the role in immune cells. Our lab has previously demonstrated that IL4R expression in breast cancer promotes the formation of metastases, as well as enhances glucose metabolism. Our overarching idea is that IL4R mediated signaling enhances breast cancer metastasis through metabolic and epigenetic alterations, and the specific hypothesis that I will test here is that signaling through the type II IL4 receptor leads to increased glucose uptake that in turn enables enhanced histone acetylation and the manifestation of a metastatic phenotype. In order to test this hypothesis, I plan to use an unbiased mass spectrometry approach in order to characterize glucose-related metabolic alterations in breast cancer initiated by IL4 signaling. A mouse model of metastatic disease will be used to determine if IL4-dependent modification of this pathway can be detected by vivo imaging of glucose uptake. I will investigate biochemical pathways that lead to histone acetylation and ultimately relate these to metastatic properties. Pharmacological inhibition as well as CRISPR/Cas9 mediated knockout of potential downstream effectors will be used in order to understand the role of specific members of an IL4R-dependent pathway in mediating metabolic and epigenetic alterations. My research will provide some answers for two of our primary questions: 1.) What are the metabolic changes mediated by IL4R and how do they contribute to metastatic progression in breast cancer; 2.) What are the epigenetic changes induced by IL4R signaling in breast cancer and how can they contribute to metastatic progression? These results will further elucidate the mechanisms that IL4 and related cytokines exploit in order to contribute to disease progression, and bolster evidence for IL4R as a novel therapeutic target in metastatic breast cancer. In addition, by understanding the downstream signaling consequences of IL4R activation in breast cancer, we can identify other novel avenues for therapy that potentially can be developed to act synergistically with IL4R.